PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis.
PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis.
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PRR14是促进肺癌发生的PI3K途径的新型激活剂。
DOI：
10.1038/onc.2016.93
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发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Yuan ZM
中科院分区：
文献类型：
--
作者：
Yang M;Lewinska M;Fan X;Zhu J;Yuan ZM
染色体局灶性扩增通常导致基因拷贝数的增加，从而导致癌症的发病。PRR 14过表达与肺癌中复发性基因座扩增相关，并且与不良预后相关。我们发现PRR 14表达的增加促进了肺癌细胞的增殖，而PRR 14表达的减少则阻碍了肺癌细胞的增殖。有趣的是，PRR 14细胞的大小明显增大，并表现出PI 3-激酶/Akt/m-TOR通路活性升高，这与对PI 3 K和mTOR抑制剂的敏感性升高有关。生物化学分析显示PRR 14作为富含脯氨酸的蛋白，与GRB 2的Src同源3（SH 3）结构域结合，导致PI 3 K活化。值得注意的是，2个癌症患者来源的PRR 14突变体显示出显著增强的GRB 2结合和增强的促进细胞增殖的能力。连同体内数据证明PRR 14和突变体的强肿瘤促进活性，我们的工作揭示了这种富含脯氨酸的蛋白质作为PI 3 K通路的新型激活剂，其促进肺癌的肿瘤发生。
Chromosomal focal amplifications often cause an increase in gene copy number contributing to the pathogenesis of cancer. PRR14 overexpression is associated with recurrent locus amplification in lung cancer, and it correlates with a poor prognosis. We show that increased PRR14 expression promoted and reduced PRR14 expression impeded lung cancer cell proliferation. Interestingly, PRR14 cells were markedly enlarged in size and exhibited an elevated activity of PI3-kinase/Akt/m-TOR pathway, which was associated with a heightened sensitivity to the inhibitors of PI3K and mTOR. Biochemical analysis revealed that PRR14, as a proline-rich protein, binds to the Src homology 3 (SH3) domains of GRB2 resulting in PI3K activation. Significantly, 2 cancer patient-derived PRR14 mutants displayed considerably augmented GRB2-binding and enhanced ability of promoting cell proliferation. Together with the in vivo data demonstrating a strong tumor-promoting activity of PRR14 and the mutants, our work uncovered this proline-rich protein as a novel activator of the PI3K pathway that promoted tumorigenesis in lung cancer.
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影响因子：
14.9
作者：
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